As the technology in the field of genetic engineering has rapidly progressed, the functions and roles of proteins and peptides have been identified and their mass production has become possible. As a consequence, many protein or peptide drugs have been commercially available, and the effort to develop new drugs by utilizing them has been continuously made.
When proteins or peptides are orally administered, it is difficult for them to pass through the intestine wall and they would be readily degenerated or decomposed by enzymes in the digestive canal, thereby providing very low bioavailability. Therefore, they are developed as a form of injectable formulation.
In case of an injectable formulation, in order to resolve patients' inconvenience due to frequent administration, various methods have been attempted to develop sustained release formulations, which can continuously provide the pharmacological effect for a long period only by a single administration. Such attempts have been disclosed in many references (Khaled Al-Tahami et al., “Smart Polymer Based Delivery Systems for Peptides and Proteins”, Recent Patents on Drug Delivery & Formulation 2007, Vol. 1, No. 1, pp. 65-71, 2007; Fei Wu et al., “Polymer-Based Sustained-Release Dosage Forms for Protein Drugs, Challenges, and Recent Advances”, AAPS Pharm Sci Tech, Vol. 9, No. 4, pp. 1 1218-1229, 2008).
Commercially available sustained release protein preparations include the products produced by applying PEGylation technology—which conjugates polyethylene glycol (PEG) with proteins—to interferon (PEGasys®, PEGintron®), GCSF (Neulasta®), asparaginase (Oncaspar®), adenosine deaminase (Adagen®), etc. However, as conjugates of PEGs having the molecular weight of 5,000 to 50,000 daltons with proteins, they are novel compounds and thus the verification of their biological safety and effectiveness is necessarily required in order for application to other proteins. Furthermore, high cost is required for their production.
In addition, sustained release preparations for peptide drugs such as leuprolide acetate (Lupron® Depot), octreotide (Sandostatin®), goserelin acetate (Zoladex®), triptorelin pamoate (Trelatar® Depot), etc. have been commercialized by using polylactic acid or polylactic acid-glycolic acid polymer—which are biodegradable polymers—as a microparticle delivery carrier. However, their effects of sustained release are still unsatisfactory.
For protein drugs, only the sustained release formulation of human growth hormone (Nutropin® Depot) has acquired the approval from USFDA. However, it was completely withdrawn from the market in 2004 because of its insufficient effect as compared with daily administration formulations.
As such, the formulations utilizing polylactic acid or polylactic acid-glycolic acid polymer microparticles for protein or peptide drug as developed up to date still have the problems such as initial burst and insufficient sustained release effect that are to be solved as sustained release formulations. Furthermore, economical factors including production cost increase due to the denaturation and big loss of drug during the production process are also the problems involved in such formulations.